Dr. Christian is an Assistant Professor in the Department of Cell and Developmental Biology. Her research program focusses on the embryonic roles of Wnt proteins in Xenopus laevis. In the project described in this proposal, she is studying the functions of two Wnt-related genes, Xwnt-8 and Xwnt-8b, in neural and mesodermal patterning. Xwnt-8 is normally expressed in presumtive ventral mesoderm. When Xwnt-8 is ectopically expressed in the dorsal mesoderm, these cells are respecified with a more ventral fate and embryos exhibit a loss of the forebrain. The initial goal of this project is to determine how misexpression of Xwnt-8 in the mesoderm perturbs pattern in the central nervous system. Two hypotheses will he tested: that misexpressed Xwnt-8 masks anterior inductive signals by retarding the involution of the dorsal mesoderm, or that it leads to a loss of mesodermally derived anterior inducing signals. A second objective is to use a subtractive hybridization approach to identify molecules that are expressed in response to, and might function downstream of, Xwnt-8 in ventral patterning. Finally, to begin functional analysis of a related Wnt, Xwnt-8b, and to examine structure/function relationships of Wnt proteins, the following aims will be completed: 1. A full length cDNA encoding Xwnt-8b will be isolated. 2. Normal expression of Xwnt-8b will be upregulated and downregulated in Xenopus embryos using ectopic expression and antisense approaches, respectively. Effects on cell fate and tissue pattern will be assessed. 3. Functional domains of Xwnt-8 and Xwnt-8b will be identified by assaying the biological activity of deletion mutant and chimeric Xwnt-8/Xwnt-8b proteins. Collectively these studies will contribute to an understanding of cellular and molecular mechanisms by which these, and possibly all, Wnts generate pattern during normal vertebrate development. Dr. Christian's responsibilities now involve teaching medical and graduate students in five different courses, as well as departmental administrative responsibilities. The award of an RCDA would relieve Dr. Christian of her substantial medical school teaching load, enabling her to devote more time to research at this crucial point in her career. In particular, it would allow her to dedicate sufficient time to her new project on post-transcriptional regulation of Wnt gene expression to develop this into an independently funded line of research. OHSU has a strong, highly collaborative research program that encourages interactions among departments.
